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Dysbiosis byproducts may make paracetamol toxic

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Andrew Whitfield-Cook ● 3 min read


Dysbiotic gut bacteria have an impact on paracetamol and other drugs' safety lending credence to the clinical relevance of conducting Liver Detoxification Profiles in patients.

The time is fast approaching where functional medicine (indeed even orthodox) practitioners will be able to assess how particular patients will respond to certain medicines. For years orthodox medicine has been critical of functional pathology, but now researchers have elucidated how dysbiotic bacteria in the intestines can produce inflammatory by-products which in-turn affect not just how drugs are able to be metabolised through the various liver detoxification pathways, but that they may in-fact have deleterious effects on organ pathology.[1-5]

Examples of this pathological process is the production of Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) which are produced solely by anaerobic bacteria fermentation of tyrosine and tryptophan, respectively, in the distal gut.[5,6] These are both nephro- and cardiovascular toxins and are highly related to a high meat and low fibre diet.[1,2,5-7] Another less studied fermentation by-product is p-cresyl-glucuronide which may add to toxic burden, especially in those with compromised liver detoxification pathways.[7



Dietary substrate


In vivo precursor


Protein-bound Uremic Toxin [6,7]


Tyrosine


Indole


Indoxyl sulphate (IS)


Tryptophan


p-cresol


P-cresyl sulphate (PCS) (and p-cresyl glucoronide)

 

Pathological effects of IS and PCS [7]:

 

Recent research into the cardiovascular effects of these by-products in Chronic Kidney Disease (CKD) patients has focussed on the use of a combination of fructooligosaccharides and probiotics to reduce adverse outcomes in these patients. The results of this trial are forthcoming.[5]

A clinically significant interplay between microbiota, the production of IS and PCS, and drug metabolism has also been noted. This lends itself favourably to the naturopathic principle of treating the gut (and its inhabitants). It also gives further validation to the clinical use of Functional Liver Detoxification Profiles which employ challenge doses of drugs (aspirin, paracetamol and caffeine) to assess the functionality of indiviudal liver pathways.[8

As noted by Wilson,[1] even pharmaceutical companies are eyeing this area of drug metabolomics as a valid and serious area for investigation to determine drug adverse-event risk. One of note, is the  increased reporting of paracetamol toxicities at both normal and even at lower than normally prescribed doses, but especially with chronic use.[4

Combining all this information together with the burgeoning waistlines in today's society, one can glean that both the dietary components  and the resident bacteria can have deleterious effects on not just the well-described sequelae of weight gain (eg.  heart disease and kidney disease) but also affect the way we can safely take our medicines. 

What is becoming increasingly obvious is that we are eating far too much protein compared to the plant-based foods essential to feeding organisms which balance out the levels of IS and PCS [3]. Further, that probiotics when combined with fibres and inulin may prove to be a useful adjunct to seemingly unrelated medicines which are detoxified through the liver's sulphation and glucuronidation pathways.[8]

PRACTICE POINTS

  1. Patients who are overweight, and/or taking medicines which are biotransformed (detoxified) through sulphation and/or glucuronidation pathways should be counselled on the benefits of a plant-based diet (eg. Mediterranean, Vegetarian, Paleolithic).
     
  2. Probiotics plus inulin may be added to therapy to assist in reducing the production of IS and PCS in the gut
     
  3. Functional and Integrative Pathology may play a role in determining if patients are at increased risk of adverse effects of medicines.
     
  4. Patients should be counselled on the possible adverse effects of even seemingly innocuous medicines, as recently noted in Australian Government funded health sites, especially when co-morbid factors are present (eg. Obesity, Diabetes, CKD).

References

  1.  Wilson ID. Drugs, bugs, and personalized medicine: pharmacometabonomics enters the ring. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14187-8. Epub 2009 Aug 19. [Full Text
     
  2. Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson JK. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A. 2009;106:14728–14733. [Full Text]  
     
  3. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012 Sep 13;489(7415):220-30. [Full Text]  
     
  4. Safe and appropriate use of paracetamol: Closing the consumer knowledge gap. Health News and Evidence. NPS Medicinewise. 2015 May 11. [Full Text] (Accessed 2015 Nov 9). 
     
  5. Rossi M, Johnson DW, Morrison M, Pascoe E, Coombes JS, Forbes JM, SYNbiotics Easing Renal failure by improving Gut microbiologY (SYNERGY): a protocol of placebo-controlled randomised cross-over trial. BMC Nephrol. 2014 Jul 4;15:106. doi: 10.1186/1471-2369-15-106. [Full Text]  
     
  6. Rossi M, Campbell KL, Johnson DW, Stanton T, Vesey DA, Coombes JS, et al. Protein-bound uremic toxins, inflammation and oxidative stress: a cross-sectional study in stage 3-4 chronic kidney disease. Arch Med Res. 2014 May;45(4):309-17. Epub 2014 Apr 18. [Abstract
     
  7. Lekawanvijit S. Role of Gut-Derived Protein-Bound Uremic Toxins in Cardiorenal Syndrome and Potential Treatment Modalities. Circ J. 2015 Sep 25;79(10):2088-97. doi: 10.1253/circj.CJ-15-0749. Epub 2015 Sep 4. [Full Text]  
     
  8.  No author. Liver Detoxification Profile- (Test Code 4010). Nutripath Integrative and Functional Pathology Services. 2015. http://nutripath.com.au/product/liver-detoxification-profile-24-hour-uri... (Accessed 2015 Nov 11). [Full Text]  

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Andrew Whitfield-Cook

Andrew is a registered nurse of 32 years, with more than 20 years experience in the natural medicine industry. Andrew is curious about, well, everything! He delights in interviewing specialist clinicians and researchers about their work and how the practical use of nutritional and herbal medicines, and physical therapies, may improve patient health.
His interests include gastroenterology, immunology and oncology. Andrew has a deep responsibility to impart the efficacious use plus the relevant safety aspects of integrative medicine to natural medicine practitioners.